Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
Diabetes. 2013 Jul;62(7):2471-80. doi: 10.2337/db12-1001. Epub 2013 Apr 8.
Conversion of one terminally differentiated cell type into another (or transdifferentiation) usually requires the forced expression of key transcription factors. We examined the plasticity of human insulin-producing β-cells in a model of islet cell aggregate formation. Here, we show that primary human β-cells can undergo a conversion into glucagon-producing α-cells without introduction of any genetic modification. The process occurs within days as revealed by lentivirus-mediated β-cell lineage tracing. Converted cells are indistinguishable from native α-cells based on ultrastructural morphology and maintain their α-cell phenotype after transplantation in vivo. Transition of β-cells into α-cells occurs after β-cell degranulation and is characterized by the presence of β-cell-specific transcription factors Pdx1 and Nkx6.1 in glucagon(+) cells. Finally, we show that lentivirus-mediated knockdown of Arx, a determinant of the α-cell lineage, inhibits the conversion. Our findings reveal an unknown plasticity of human adult endocrine cells that can be modulated. This endocrine cell plasticity could have implications for islet development, (patho)physiology, and regeneration.
将一种终末分化的细胞类型转化为另一种类型（或转分化）通常需要强制表达关键转录因子。我们在胰岛细胞聚集体形成模型中研究了人胰岛素产生β细胞的可塑性。在这里，我们显示原代人β细胞可以在不引入任何遗传修饰的情况下转化为产生胰高血糖素的α细胞。该过程在几天内发生，如慢病毒介导的β细胞谱系追踪所示。基于超微结构形态，转化细胞与天然α细胞无法区分，并在体内移植后保持其α细胞表型。β细胞向α细胞的转化发生在β细胞脱颗粒之后，其特征是β细胞特异性转录因子 Pdx1 和 Nkx6.1 在胰高血糖素（+）细胞中存在。最后，我们表明，慢病毒介导的 Arx（α细胞谱系的决定因素）敲低抑制了转化。我们的发现揭示了人类成年内分泌细胞的未知可塑性，可以进行调节。这种内分泌细胞的可塑性可能对胰岛发育、（病理）生理学和再生具有重要意义。
